In the phase II DESTINY-Lung01 trial, presented at the European Society for Medical Oncology (ESMO) Congress 2021 (Abstract LBA45) and concurrently reported in The New England Journal of Medicine, Bob T. Li, MD, PhD, MPH, and colleagues found that fam-trastuzumab deruxtecan-nxki produced durable responses in a high proportion of patients with previously treated HER2-mutant non–small cell lung cancer (NSCLC).

As noted by the investigators, no HER2-targeted therapies have been approved for treatment of patients with NSCLC.

Bob T. Li, MD, PhD, MPH

Study Details

The trial enrolled 91 patients with unresectable or metastatic nonsquamous NSCLC with disease relapsing during or refractory to standard treatment. They were recruited from sites in North America, Japan, and Europe between May 2018 and July 2020. Enrollment of patients with asymptomatic brain metastases who were not receiving ongoing glucocorticoid or anticonvulsant therapy was permitted. Patients received fam-trastuzumab deruxtecan-nxki at 6.4 mg/kg every 3 weeks. The median number of prior therapies was two; 95% of patients had received platinum-based therapy and 66% had received anti–PD-1 or anti–PD-L1 treatment. The primary outcome measure was objective response on independent central review. 

Responses

Median follow-up was 13.1 months (range = 0.7–29.1 months). Objective response was observed in 50 patients (55%, 95% confidence interval [CI] = 44%–65%), with complete response observed in one. Stable disease ≥ 6 weeks was observed in an additional 34 patients (37%), yielding a disease control rate of 92%. Median time to response was 1.5 months (range = 1.2–9.3 months). Median duration of response was 9.3 months (95% CI = 5.7–14.7 months).

Among 33 patients with baseline central nervous system metastases, 18 (55%) had objective response, including 8 of 14 who had previously received radiotherapy to the brain and 10 of 19 who had not. Responses were observed in patients with different HER2 mutation subtypes across three exon locations and in patients with no detectable HER2 expression or who were negative for HER2 amplification.

Median progression-free survival was 8.2 months (95% CI = 6.0–11.9 months) and median overall survival was 17.8 months (95% CI = 13.8–22.1 months). Among the 33 patients with central nervous system metastases, median progression-free survival was 7.1 months (95% CI = 5.5–9.8 months) and median overall survival was 13.8 months (95% CI = 9.8–20.9 months).

Adverse Events

Grade ≥ 3 drug-related adverse events occurred in 46% of patients, the most commonly reported being neutropenia (19%), anemia (10%), nausea (9%), and fatigue (7%). Serious drug-related adverse events occurred in 20% of patients. Drug-related adverse events led to discontinuation of treatment in 25%, including pneumonitis in 13% and interstitial lung disease in 5%. Adjudicated drug-related interstitial lung disease occurred in 26% of patients. Treatment-related death occurred in two patients, with both deaths due to interstitial lung disease.

The investigators concluded: “[Fam]-trastuzumab deruxtecan-[nxki] showed durable anticancer activity in patients with previously treated HER2-mutant NSCLC. The safety profile included interstitial lung disease that was fatal in two cases. Observed toxic effects were generally consistent with those in previously reported studies.”

Disclosure: The study was funded by Daiichi Sankyo and AstraZeneca. For full disclosures of the study authors, visit nejm.org.